Oxazole formamidines of primary amines



United States Patent 3,133,078 OXAZOLE FORMANHDINES OF PRIlVlARY AMDJESNorbert Steiger, Nutley, N.J., assignor to Hofimann- Ft Roche Inc.,Nutley, N.J., a corporation of New ersey No Drawing. Filed Nov. 20,1961, Ser. No. 153,694 3 Claims. (Cl. 260-307) This invention relates toa process for the production of formamidines from primary amines and tothe novel compounds produced by the process.

The process of this invention comprises reacting a nonaliphatic primaryamine or a hydrohalide thereof with formamide or a lower alkyl formamidein the presence of an arylsulfonyl halide or a thionyl halide to producethe formamidine of the primary amine as illustrated by the followingreaction schemes:

1 HX AIYLSOaH R-NHg SOXZ 'i' HCON In the above formulae R represents acyclic group, X represents halogen and R and R each represents hydrogenor lower alkyl.

The cyclic groups represented by R in the formula above areunsubstituted or substituted monocyclic or polycyclic groups containingfive or more atoms and at least one double bond in the ring system. Oneor more electronegative groups may be attached to the ring. These cyclicgroups include aromatic hydrocarbons, hydroaromatic hydrocarbons,nitrogen-, oxygenor sulfur-heterocyclics containing at least oneunsaturated linkage, and fused hydrocarbon or heterocyclic ring systemscontaining at least ones unsaturated linkage in the ring system.Illustrative of the diiferent types of cyclic groups, i.e., thoserepresented by R in Formula I, are the following: phenyl, anthraquinone,biphenyl, pyridine, quinoline, pyrimidine, isoxazole, thiazole,triazine, uracil, benzothiazole, etc. The ring systems described abovemay hear one or more substituents, e.g., carboalkoxy groups such ascarbo-lower alkoxy, for example COOCH and di-lower alkylaminocarbo-loweralkoxy, for example, COOC H N(C H alkylamino; acylamino groups such aslower alkanoylamino, for example, NHCOCH ether and thioether groups suchas lower alkoxy and lower alkylrnercapto, for example, CH O, C H O, anddi-lower alkylamino-lower alkoxy, for example, (C H NC H O; alkylgroups, preferably lower alkyl such as methyl, ethyl, propyl, etc.;electronegative acid radicals derived from organic or inorganic acids,such as the halogens, S0 N0 OH, COOH, SO H, sulfamyl, acyl groups suchas 3,133,678 Patented May 12, 1964 ice lower alkanoyl groups, forexample, CH CO, aroyl groups such as benzoyl and substituted benzoylgroups, such as trifluoromethylbenzoyl, arsonyl, thiocyano, and thelike.

The primary amino group which takes part in the condensation reactionmust be directly attached to the cyclic portion of the molecule. One ormore such primary amino groups present on the nucleus may react. Asindicated above, it is also necessary that there be at least oneunsaturated linkage in the ring system. The aryl sulfonyl halide whichmust be present includes benzenesulfonyl halides, toluenesulfonylhalides, xylenesulfonyl halides, etc., preferably the first two,especially the chlorides thereof. Thionyl halides such as thionylchloride may also be used. Preferably monoalkyl formamide, such asmethylformamide, and dilower-alkyl formamide, such as dimethylformamide,diethylformamide, etc. are used in the process, lower alkyl formamides,in particular. Compounds bearing very strongly electronegativesubstituents, e.g., p-nitroaniline, react also with formamide.

When the primary amine contains one or more electronegative substituentson the ring, either the free base itself or its hydrohalide willordinarily react according to the process of this invention. amines,such as aminopyridine, aminoquinaldine, aniline, p-phenetidine, etc.,however, readily form sulfonamides with benzenesulfonyl halides ortoluenesulfonyl halides, especially in the presence of an acid bindingagent such as pyridine and even formamide or dimethylformamide. In orderto produce formamidines from such strongly basic amines according to theprocess of this invention,

it is therefore usually in this instance to use as starting In generalthe reaction proceeds at room temperature and is exothermic. The primaryamine and arylsulfonyl halide or thionyl halide are merely admixed inexcess formamide compound, the latter acting also as reaction medium. Itis convenient in some instances to apply heat in order to accelerate andcomplete the reaction, but the temperature should not exceed C.

In many instances the hydrohalide or arylsulfonate salt of theformamidine will precipitate directly from the reac-' tion mixture uponcooling. It is preferable, however, to add to the reaction mixture aninert organic solvent such as alcohol, acetone, benzene, etc., in orderto complete the crystallization of the product and to effect the removalof impurities and excess formamide compound. In general, the strongeramines tend to produce hydrohalic salts and the weaker amines tend toproduce sulfonates. The acid salts may be converted to the free base byneutralization with a basic reagent such as aqueous sodium carbonate,sodium hydroxide, etc. Any other acid salt may be obtained from the freebase by treatment with an equivalent proportion of the appropriateorganic or inorganic acid. There may thus be obtained such acid additionsalts of the formamidines as the hydrohalides,

Strongly basic primary 2% benzenesulfonates, toluenesulfonates,nitrates, sulfates, phosphates, citrates, tartrates, succinates, etc.

Listed below by structural formula are groups of novel compounds whichmay be produced according to this invention. The cyclic groups may bearone or more of the substituents described above.

More particularly the novel compounds to which this invention relatesare selected from the group consisting of compounds of the formuladenoted XIV, wherein R and R each represents a member of the groupconsisting of hydrogen and lower alkyl, monovalent radical ringsubstituted derivatives thereof and salts of said compounds.

The monovalent radical ring substituents above referred to, besidesother forrnamidino groups, are preferably such groups as carboalkoxygroups such as carbo-lower alkoxy, for example COOC H and di-loweralkylaminocarbolower alkoxy, for example, COOC H N(C l-l alkylamino suchas lower alkylarnino and di-lower alkylamino; acylamino groups such aslower alkanoylamino, for example, NHCOCH ether and thioether groups suchas lower alkoxy and lower alkylmercapto, for example, (EH 0, C H O, anddi-lower alkylamino-lower alkoxy, for example, (C H NC H O; alkylgroups, preferably lower alkyl such as methyl, ethyl, propyl, etc.;electronegative acid radicals derived from organic or inorganic acids,such as the halogens, S0 N0 OH, COOH, SO H, sulfamyl, acyl groups suchas lower alkanoyl groups, for example, CH CQ, aroyl groups such asbenzoy] and sub- Example 1 25 g. of p-diamino-diphenyl-sulfone weredissolved in cc. of dimethylforrnamide. 55 g. of p-tolueuesulfonylchloride were added and the mixture was stirred. The mixture was stirredfor about one hour. The temperature rose to 74. The reaction mixture wasthenpoured into 800 cc. of water and 60 cc. of 40% sodium hydroxide. Themixture was stirred for 2 hours 'and then filtered. The crudecrystalline product thus obtained was recrystallized by dissolving in250 cc. of boiling benzene, filtering oil the insoluble impurities andadding 400 cc. of Skellysolve B (an n-hexane fraction) to the benzenefiltrate. The mixture was kept overnight in the refrigerator. Thecrystalline N,N- (p,p'-sulfonyldiphenylene bis[N",N"-dimethylformamidine] thus obtained melted at 131 to 133.

The procedure described in the preceding paragraph was repeatedsubstituting 50 g. of benzenesulfonyl chloride for the 55 g. ofp-toluenesulfonyl chloride. The same product was obtained.

100 cc. of dimethylformamide, 25 g. of p-diamino-diphenyl-sulfone and 50g. of p-toluenesulfonyl chloride were reacted as described in the firstparagraph above. After the temperature dropped to 40, 200 cc. of alcoholwere added and the mixture was heated to reflux. The clear solutionwhich resulted was filtered while hot. 100 cc. of alcohol were added tothe filtrate which was permitted to crystallize in the refrigerator.There was obtained white, crystalline N,N-(p,p-sulfonyldiphenylene)bis[N",N"-dimethylformamidine] p-toluenesulfonate.

Example 2 29 g. of mono-acetyldiamino-diphenyl-sulfone, 50 cc. ofdimethylformamide and 22 g. of benzenesulfonyl chloride were stirredtogether, the temperature rising to 64. The mixture was then stirred forone hour at 60. The reaction mixture, was then drowned in 1000 cc. ofwater. While stirring, cc. of a 20% sodium carbonate solution weredropped in to neutralize the acid. After 24 hours the solid obtained wasfiltered, the filter cake was washed with ice water and sucked dry on afunnel. The solid was then dried at 70. The p-acetamidophenyl-p-(dimethylamino-methyleneamino) phenyl sulfone-was then crystallized from75% acetic acid, M.P. 2'10 to 262.

Example 3 27 g. of procaine hydrochloride and 25 g. of p-toluene ridecrystallized as white crystals, M.P. 205 to 206,

from isopropanol-ethanol.

Example 4 30 g. of p-aminoacetanilide and 50 g. of p-toluenesuL fonylchloride in 70 cc. of dirnethylformamide were stirred and heated for onehour in a boiling water bath.

The mixture was diluted with 50 cc. of alcohol, refluxed for 1 /2 hours,diluted with 300 cc. of acetone and filtered at The white, crystallineN-(p-acetamidophenyl)- N',N-dimethylformamidine hydrochloride, M.P. 273to 274, was recrystallized from methanol.

Example 5 28 g. of anthranilic acid and 50 g. of p-toluenesulfonylchloride in 80 cc. of dimethylformamide were reacted at 90 for one hour.100 cc. of alcohol were added, the mixture was refluxed for minutes andthen cooled to 10. N (o-carboxyphenyl)-N',N-dimethylformamidinehydrochloride crystallized. The white, crystalline hydrochloride wasrecrystallized from 80% alcohol, M.P. 169 to 171.

Example 6 N-(p-carboxyphenyl)-N',N'-dirnethylformamidine hydrochloride,obtained as white crystals melting at 236 to 237 upon crystallizationfrom 93% alcohol, was produced from 28 g. of p-aminobenzoic acidaccording to the procedure described in Example 5.

Example 7 15.5 g. of p-aminosalicylic acid and 25 g. ofp-toluenesulfonyl chloride in 50 cc. of dimethylformamide were stirredtogether. The temperature rose to 62. The mixture was diluted with 100cc. of alcohol and permitted to crystallize. TheN-(4-carboxy-3-hydroxyphenyl)-N, N'-dimethylformamidinep-toluenesulfonate obtained was recrystallized from 90% ethanol, M.P.235.

Example 8 33 g. of o-aminophenol and 70 g. of p-toluenesulfonyl chloridewere reacted in 100 cc. of dimethylformamide. The temperature rose to70. The mixture was then heated one hour at 85. 25 cc. of alcohol wereadded to the reaction mixture and it was refluxed for /2 hour. 300 cc.of acetone were added at and the mixture was chilled to 10. TheN-(o-hydroxyphenyl)-N',N'-dirnethylforrnamidine hydrochloride wasrecrystallized from alcohol and precipitated as white crystals, M.P.156.

Example 9 According to the procedure described in Example 8, there wasobtained from 33 g. of m-aminophenol, N-(mhydroxyphenyl)N,N'-dimethylformamidine hydrochloride as grayish crystals, M.P. 241upon crystallization from 95% alcohol.

Example 10 22 g. of p-aminophenol and g. of p-toluenesulfonyl chloridewere stirred in 100 cc. of dirnethylformamide. The temperature rose toThe -mixture was then heated for one hour at 90. 200 cc. of ether wereadded and, after stirring in an ice bath, the ether layer was decantedoff. 300 cc. of acetone were added and the mixture was permitted tocrystallize in the refrigerator. TheN-(p-hydroxyphenyl)-N',N'-dimethylforrnamidine ptoluenesulfonate wasrecrystallized from alcohol, M.P. 209 to 210.

Example 11 18 g. of 4-chloro2-nitroaniline and 22 g. ofp-toluenesulfonyl chloride were stirred in 50 cc. of dimethylformamide,the temperature rising to 51. The mixture was then heated for one hourat 80 to 85. 300 cc. of acetone were added at 40 and the precipitatewhich formed was filtered oil. TheN,N-dimethyl-N'-(4-chloro-2-nitrophenyl)formamidine hydrochloride wasrecrystallized from 95% alcohol, M.P. 205.

Example 12 16 g. of 4-nitro-2-aminotoluene and 25 g. of ptoluenesulphonyl chloride were stirred in 50 cc. of dimethyL formamide,the temperature rising to 63. The mixture was then stirred at roomtemperature for one hour. 300 cc. of acetone were added and the mixturewas placed in the refrigerator to crystallize. The N,N-dimethyl-N- 6(Z-methyI-S-nitmphenyl)formamidine hydrochloride was recrystallized fromalcohol, M.P. 205

Example 13 17 g. of 4-methoxy-2-nitroaniline and 25 g. ofp-toluenesulfonyl chloride in 25 cc. of dimethylformamide were reactedas described in Example 12. The N,N-dimethylN-(2-nitro-4-methoxyphenyl)-formamidine hydrochloride was crystallizedfrom acetonitrile, M.P. 198 to 200.

Example 14 26 g. of m-chloroaniline and 50 g. of p-toluenesulfonylchloride in 70 cc. of dimethylformamide were stirred together, thetemperature rising to 74. cc. of alcohol were added, the mixture washeated /2 hour to reflux and then filtered.N-(3-chlorophenyl)-N',N-dimethylformamidine hydrochloride crystallizedfrom the filtrate. Upon recrystallization from acetonitrile-alcohol, theWhite crystalline hydrochloride melted at 233.

Example 15 Example 16 32 g. of 3,4-dichloroaniline and 45 g. ofbenzenesulfonyl chloride in 100 cc. of dimethylformamide were stirredtogether, the temperature rising to 60. The mixture was stirred for 2hours at 60 and then diluted with 300 cc. of acetone. The mixture wasthen filtered at room temperature. TheN-(3,4-dichlorophenyl)-N,N-dimethylformamidine hydrochloride thusobtained, upon recrystallization from 90% alcohol, melted at 255 to 256.

Example 17 20 g. of 2,4,5-trichloroaniline and 25 g. ofp-toluenesulfonyl chloride in 50 cc. of dimethylformamide were stirredat room temperature for one hour, then heated at 85 for one hour. Themixture was cooled to 40 and 200 cc. of acetone were added. CrystallineN,N-dimethyl- N (2,4,5 trichlorophenyl)formamidine hydrochlorideprecipitated. The product was filtered, washed with acetone and dried at70. Upon recrystallization from acetonitrile-methanol, the productmelted at 225 to 227.

The hydrochloride obtained above Was dissolved in water and madealkaline with 1 N sodium hydroxide. The free base,N,N-dimethyl-N-(2,4,5-trichlorophenyl)formarnidine, was obtained aswhite crystals, M.P. 85 after recrystallization from acetonitrile.

Example 18 41 -g. of 2,6-dichloro-4-nitroaniline land 42 g. ofhenzenesulfonyl chloride in 100 cc. of dimethylformamide Were stirredtogether, the temperature rising to 42. The mixture was heated in awater bath for one hour at 90. 50 cc. of alcohol were added, the mixturewas refluxed for 15 minutes, cooled to 40 and 400 cc. of acetone wereadded. The precipitate which formed was filtered dissolved in 250 cc. ofwater and 25 cc. of concentrated hydrochloric acid at room temperatureand filtered again.- The filtrate was neutralized with approximately 40cc. of sodium hydroxide. The crystalline N,N-dimethyl-N'-(2,6-dichloro-4-nitrophenyl)-formamidine wasrecrystallized from alcohol,M.P. to 162.

Example 19 15 g. of [aniline hydrochloride and 25 g. of benzenesul-fonylchloride in 50 cc. of dimethylformamide were erator to crystallize.

stirred at room temperatlne for one hour. The mixture was then heated ina water bath at 80 until a sample, treated with 1 N-HCl and 1 N-NaNOshowed no diazo reaction. The mixture was cooled to room temperature,200 cc. of acetone were added and the mixture was stirred in an icebath. The crystalline N-phenyl-N,N'-dimethylformamidine hydrochloridewhich precipitated was filtered, dried at 75 and recrystallized fromisopropanol, M.P. 223 to 225".

The free base, N-phenyl-N',N-dimethylformamidine, was obtained bytreating the hydrochloride with a dilute solution of sodium hydroxide,extracting with ether, concentrating the ether solution and distillingthe ether concentrate in vacuo. The base was obtained as a colorlessoil, B.P. 75 to 76/0.02 mm.

Example 20 35 g. of p-phenetidine hydrochloride and 50 g; ofptoluencsulfonyl chloride in 60cc. of dimethylformamide were stirredtogether, the temperature rising to 64. The diazo reaction of the masswas negative. The mixture was diluted with 400 cc. of acetone and placedin the refrig- The mixture was filtered and theN-(p-ethoxyphenyl)-N',N-dimethylformamidine p-toluenesulfonate wasrecrystallized from isopropanol, M.P. 169 to 170.

Example 21 28 g. of o-nitroaniline and 45 g. of p-toluenesulfonylchloride in 100 cc. of dime-thylformamide were stirred together, thetemperature rising to 60. The mixture was then stirred and heated in awater bath for one hour at 90 to 95. The reaction mixture was thendiluted at 80 with 300 cc. of benzene and chilled to TheN-(onitrophenyl)-N,N'-dimethylformamidine hydrochloride whichprecipitated was filtered off, washed with benzene and recrystallizedfrom acetonitrile-ethanol, M.P. 224 to 225.

Example 22 28 g. of p-nitroaniline and 45 g. of p-toluenesulfonylchloride in 150 cc. of dirnethylformamidc were stirred together, thetemperature rising to 62. When the temperature had fallen to 40, thereaction mixture was heated at 85 for one hour. The mixture was dilutedwith 300 cc. of alcohol, refluxed until a clear solution was obtainedand the solution was filtered hot. The N-(p-nitrophenyl)-N,N'-dimethylformamidine p-toluenesulfonate crystallized from thefiltrate, M.P. 240 to 242.

42 g. of N-(p-nin'ophenyl)-N,N-dimethylform=arnidlne p-toluenesulfonatewere dissolved at 90 in 500 cc. of water and the solution was filteredwhile hot. The filtrate was made alkaline. with about 30 cc. of sodiumhydroxide. The free base, N- (p-ni-trophenyl)-N,N-dimethylformarnidine,precipitated and was recrystallized from benzene-Skellysolve B, M.P. 79to 80.

Example 24 22 g. of arsanilic acid and 50 cc. of dimethylforrnamide werestirred together. 25 g. of p-toluenesulfonyl chloride were added withthe temperature rising to 60. The reaction mixture was heated foronehour at 80, /2 hour at 95 and another half hour at 105. The mixturewas cooled to 30, diluted with 250 cc. of acetone and then 8 chilled to10. The mixture was filtered after 2 hours and the residue was washedwith acetone. The 4-(N,N-dimethylformamidino)henzenearsonic acidhydrochloride was crystallized from dilute alcohol, M.P. 221 to 222.

Example 20 g. of l am'ino-anthraquinone and g. of p-toluenesulfonylchloride in 100 cc. of dimethylfornramide were heated at 95 forone hour.The mass was diluted with 250 cc. of alcohol, refluxed until a clearsolution wasobtained and filtered while hot. 1-(N,N-dimethylforrnamidino)anthraquinone toluenesulfonate crystallized from the filtrate, M.P.185.

Example 26 37.5 g. of o-tolylazo-o-toluidine hydrochloride and g. ofp-toluenesnlfonyl chloride in 100 cc. of dimethylformam ide were stirredtogether, the temperature rising to The mixture was heated at 90 for onehour and then diluted at 50 with 300 cc. of water. The mixture wasstirred for 3 hours, filtered and the residue was washed with a littleice water. The 5-o-tolylazo-2-(N,N-dimethylformamidinofioluenep-toluenesulfonate was dried in vacuo at and crystallized from alcohol,M.P. 166 to 167.

Example 27 Example 28 17 g. of diarrisidine hydrochloride and 20 g. ofbenzenesulfonyl chloride in 50 cc. of dimethyltormamide were stirred atroom temperature for one hour, then heated at 85 for an additional hour.The diazo reaction was then negative. The mixture was diluted at 60 with200 cc. of acetone, cooled to 10 and filtered. TheN,N'-bis[dimethylaminomethylene]4,4 o-dianisidine dihydrochloride wascrystallized from alcohol, M.P. 268 (with dec.).

Example 29 24 g. of p-arninoazobenzene hydrochloride and 25 g. ofp-toluenesulfonyl chloride in 50 cc. of dimethylforrnamide were stirredtogether, the temperature rising to 56. The mixture was heated for /2hour at 80 diluted with 175 cc. of alcohol, heated to reflux for /2 hourand the clear solution was then filtered while hot.p(Dimethylarninomethyleneamino) azobenzene p-toluenesulfonatecrystallized from the filtrate, M.P. 198 to 199.

Example 30 Hydrogen chloride gas was passed into a suspension of 47 g.of Z-aminopyridine in 300 cc. of toluene at a temperature of 5 to 15 C.until saturated. Z-aminopyridine dihydrochloride separated as an oil.The oil was added to 200 cc. of dimethylformamide. 130 g. ofp-toluenesulfonyl chloride were added with stirring. The mixture wasstirred at room temperature for one hour and then at 60 for 2 hours. Itwas then cooled to 20, diluted with 400 cc. of acetone and chilled to10. The white, crystalline 2-(N,N-dimethylformamidino)pyridinedihydrochloride was then filtered off and recrystallized frommethanol-acetone, M.P. 178.

Example 31 37 g. of 2,6-diaminopyridine hydrochloride and g.of'p-toluenesulfonyl chloride in 100 cc. of dimethylformamide werestirred together, the temperature rising to The mixture was stirred at80 for one hour, 50 cc. of alcohol were added and the mixture wasrefluxed for /2 hour. 200 cc. of acetone were added at 20, the mixturewas stirred for one hour and then filtered at 10. The filter cake wasdried in a desiccator over sulfuric acid. The2,6-bis-(N,N-dimethylformamidino)pyridine dihydrochloride wascrystallized from methanol-acetone, M.P. 289 to 290.

Example 32 26 g. of 6-rnethoxy-8-aminoquinoline hydrochloride and 25 g.of benzenesulfonyl chloride in 100 cc. of dimethylformamide were stirredtogether, the temperature rising to 61. The mixture was heated at 80 forone hour, diluted at 60 with 300 cc. of acetone, chilled to 10 andfiltered. The 6 -methoxy 8 (dimethylaminomethyleneamino)quinolinedihydrochloride, upon crystallization from 90% alcohol, melted at 210 to212.

The free base, 6-methoxy-8-(dimethylaminomethyleneamino)-quinoline, wasobtained by dissolving the dihydrochloride obtained above in water andmaking the solution alkaline with 1 N sodium hydroxide. The free basecrystallized from acetonitrile in the form of white needles, M.P. 158.

Example 33 21.5 g. of 4,6-diaminoquinaldine dihydrochloride and 35 g. ofp-toluenesulfonyl chloride in 150 cc. of dimethylformamide were stirredfor one hour at room temperature. The mixture was stirred at 90 for onehour. The diazo reaction was negative. The mixture was diluted at 60with 300 cc. of acetone, cooled to 20 and the precipitate was filteredoff. The -(dimethylaminomethyleneamino)-4-aminoquinaldinedihydrochloride was crystallized from dilute alcohol, M.P. 288.

The free base, 6-(dimethylaminomethyleneamino)-4- amino-quinaldine, wasobtained by dissolving the dihydrochloride obtained above in water andmaking the solution alkaline with sodium hydroxide. The free base wasobtained as ofi-white crystals upon crystallization from acetonitrile,M.P. 223 to 224.

Example 34 26 g. of 2-aminopyrimidine hydrochloride and 42 g. ofbenzenesulfonyl chloride in 50 cc. of dimethylformamide were stirredtogether, the temperature rising to 41. The mixture was heated at 90 forone hour and then diluted at 40 with 300 cc. of acetone.N,N-dimethyl-N'-(2-pyrimidyl)formamidine hydrochloride crystallized andwas filtered at 10. The hydrochloride was recrystallized fromacetonitrile, M.P. 212.

Example 35 23 g. of -amino-3,4-dimethylisoxazole and 50 g. ofp-toluenesulfonyl chloride in 50 cc. of dimethylformamide were stirredtogether, the temperature rising to 75. The mixture was heated for onehour at 85. It was then diluted at 30 with 400 cc. of acetone andfiltered at The residue,N,N-dimethyl-N'-(3,4-dimethyl-5-isoxazolyl)formamidinep-toluenesulfonate was crystallized from alcohol, M.P. 145.

Example 36 g. of Z-aminothiazole and 50 g. of p-toluenesulfonyl chloridein 50 cc. of dimethylformamide were stirred together, the temperaturerising to 61. The mixture was heated for /2 hour at 85. It was thendiluted with 400 cc. of acetone at 60 and chilled to 10. The white,crystalline N,N-dimethyl-N-(2-thiazolyl)formamidine hydrochloride wasfiltered and recrystallized from isopropanolacetone, M.P. 168 to 170.

Example 37 21 g. of N,N-diallylmelamine and g. of p-toluenesulfonylchloride in 100 cc. of dimethylformamide were stirred for one hour atroom temperature. The mixture was heated for /2 hour at 60, one hour at80 and then /2 hour at 85 At room temperature it was diluted with 300cc. of water and cc. of 40% sodium hydroxide.

10 The mixture was stirred for 2% hours at room temperature and thewhite precipitate was then filtered oif. The 2-diallylamino-4-amino-6-(N,N-dimethylformamidine) -S- triazine was crystallized fromacetonitrile, M.P. 174.

Example 38 2.5 g. of S-aminouracil and 5 g. of p-toluenesulfonylchloride and 6 cc. of dimethylformamide were heated in a water bath atThe melt was diluted with 4 cc. of alcohol and 20 cc. of acetone. Theprecipitated 5-(dimethylaminomethyleneamino) 2,4- dioxo 1,2,3,4-tetrahydropyrimidine hydrochloride was filtered at 10 and crystallizedfrom 85% ethanol, M.P. higher than 350.

- Example 39 14 g. of p-nitroaniline and 22 g. of p-toluenesulfonylchloride in 50 cc. of formamide were stirred together, the temperaturerising to 50. The mixture Was then stirred at 60 for one hour and 70 for2 hours. cc. of alcohol were added and the mixture was heated to reflux.The clear solution was filtered while hot. N-(p-nitrophenyl)formamidinep-toluenesulfonate crystallized from the filtrate and was recrystallizedfrom alcohol, M.P. 202.

The procedure described above was repeated utilizing 20 g. ofbenzenesulfonyl chloride to obtain N-(p-nitrophenyl)formamidinebenzenesulfonate, M.P. 225 to 227.

Example 40 20 g. of p-nitroaniline, 35 g. of p-toluenesulfonyl chlorideand 50 cc. of diethylformamide were heated in a boiling water bath forone hour until a clear light yellow solution was formed. The solutionwas diluted with 100 cc. of alcohol, heated to reflux for 15 minutes andfiltered while hot. The filtrate was cooled to 10 and 200 cc. of icewater were added. N-(p-nitrophenyl)-N',N'-diethylformamidine p-toluenesulfonate crystallized in needles. The compound was filtered,washed with a little ice water, dried in the oven and recrystallizedfrom dilute. alcohol. M.P. to 162.

The free base, N-(p-nitrophenyl)-N',N-diethylformamidine, was obtainedby dissolving the p-toluenesulfonate in water, filtering and making thefiltrate alkaline with aqueous sodium carbonate solution. The yellow,crystalline base melted at 59 to 60.

Example 41 2 g. of p-nitroaniline, 3.5 g. of p-toluenesulfonyl chlorideand 5 cc. of methylformamide were heated for /2 hour in a boiling waterbath. The mixture was diluted with 15 cc. of alcohol, heated untilsolution was obtained and then filtered while hot.N-(p-nitrophenyl)-N'-rnethylforrnamidine p-toluenesulfonate crystallizedfrom the filtrate. Upon recrystallization from alcohol, the compoundmelted at Example 42 41 g. of 2-amino-6-hydroxybenzothiazole and 50 g.of p-toluenesulfonyl chloride in 100 cc. of ,dimethylformamide werestirred together, the temperature rising to 65. The mixture was heatedand stirred for 2 hours at 80. It was diluted at 60 with 300 cc. ofacetone. 2- (N,N-dimethy1formamidino)-6-hydroxybenzothiazolehydrochloride precipitated, Was filtered and dried, M.P. 230. 15 g. ofthe hydrochloride obtained above were dis solved in 200 cc. of water at60 and filtered. 50 cc. of sodium acetate solution (20%) were added tothe filtrate. The free base,2-(N,N-dimethylformamidino)-6-hydroxybenzothiazole, precipitated, Wasfiltered off and dried, M.P. 237.

Example 43 22 g. of 2-(N,N-dimethylformamidino)-6-hydroxybenzothiazole,300 cc. of chlorobenzene, 7 g. of sodium methoxide and 50 cc. ofmethanol were stirred for one hour at room temperature. The methanol wasthen distilled oil. 20 g. of diethylaminoethyl chloride were added at 90and the reaction mass was heated for 3 hours to refiux at'130. It wasthen cooled below 100, 200 cc. of water and cc. of sodium hydroxide wereadded and the mixture was stirred for one hour. The chlorobenzene layerwas separated, dried with sodium sulfate, filtered and concentrated invacuo. The oily residue was crystallized from acetonitrile andrecrystallized from benzine (RP. 30 to 60). The yellow crystalline2-(N,N-dimethylform amidino) -6-( p diethylaminoethoxy)benzothiazolemelted at 69 to 70.

The free base obtained above was converted into the oxalate by mixing anether solution of the base with an ether solution of oxalic acid. Theoxalate precipitated and was crystallized from methanol, M.P. 162 to163.

Example 44 34 g. of 3-aminopyridine dihydrochloride and 45 g. ofp-toluenesulfonyl chloride in 100 cc. of dimethylformamide were stirredtogether, the temperature rising to 71. The mixture was heated for onehour at 80. It was diluted at 40 with 300 cc. of acetone and chilled to10. The crystalline precipitate, 3-(N,N-dimethyltormamidino)pyridinedihydrochloride was filtered and recrystallized from methanol-ethanol,M.P. 228 (with dec.).

Example 45 26 g. of 4-aminopyridine hydrochloride and 44 g. ofp-toluenesulfonyl chloride in 100 cc. of dimethylformamide were stirredtogether, the temperature rising to 38. The mixture was heated for 2hours at 60. A sandy pre cipitate formed. The mixture was diluted with300 cc. of acetone, chilled to 10 and filtered.4-(N,N-dimethylformamidino)pyridine dihydrochloride was obtained aswhite crystals, M.P. 260 to 261 (with dec.), upon crystallization frommethanol-acetonitrile.

Example 46 13 g. of 2amino-5-nitrothiazole hydrochloride and 22 g. ofp-toluenesulfonyl chloride in 50 cc. of dimethylformamide were stirredtogether, the temperature rising to 47. The reaction mixture was stirredand heated for 2 hours at 80 to 85. It was diluted at 40 with 200 cc. ofacetone, chilled to 10 and filtered. The residue was dried at 75 andcrystallized from acetonitrile. The 2-(dimethylaminomethyleneamino-5-nitrothiazole hydr ochloride melted at 178 to 180.

Example 47 25 g. of p diamino-diphenyl-sultone and 50 cc. ofdimethylformamide were stirred. 26 g. of thionyl chloride were droppedin at a temperature below The mixture was stirred for one hour at roomtemperature, 2 hours at 60 to 65 and 2 hours at 80 to 90. The diazoreaction was negative. The mixture was diluted at room temperature with150 cc. of water and filtered through a folded filter. The filtrate wasmade alkaline with sodium hydroxide. The white precipitate,N,N'-(p,p'-sulfonyldiphenylene) bis [N",N"-dimethylformamidine], wasfiltered, washed with water, dried and crystallized from Skellysolve C(a normal heptane fraction), M.P. 130 to 133.

Example 48 22 g. of p-aminophenol and 50 cc. of dimethylformamide werestirred. 26 g. of thionyl chloride were dropped in at a temperaturebelow 20. The mixture was stirred for one hour at room temperature, thenheated one hour at 60, one hour at 80 and 2 hours at 95. The diazoreaction was negative. The mixture was diluted with cc. of alcohol and200 cc. of acetone. An additional 400 cc. of acetone were added and themixture was placed in the refrigerator to crystallize. TheN-(p-hydroxyphenyl)-N',N-dimethylformamidine hydrochloride wasrecrystallized from methanol-acetone, M.P. 198 to 200. By treatment ofthe hydrochloride with sodium carbonate solution, N (p hydroxyphenyl)N',N' dimethylform- 12 amidine precipitated. The free base wascrystallized from alcohol, M.P. 197 to 199.

69 g. of p-phenetidine hydrochloride and 100 cc. of dimethylformamidewere stirred. 52 g. of thionyl chloride were dropped in at a temperaturebelow 20. The temperature was permitted to rise slowly to 30. Themixture was then heated in a water bath to 40, one hour at 60, one hourat and one hour at The diazo reaction was then negative. The mixture wasdiluted with 200 cc. of water and then made alkaline at 15 to 22 with150 cc. of sodium hydroxide and 25 cc.

of sodium carbonate (20% 300 cc. of ether were added.

42 of p-nitroaniline and 100 cc. of dimethyltormamide were stirred. 39g. of thionyl chloride were added at a temperature below 20. The mixturewas heated to 30 and the temperature then rose to 68.N-(p-nitrophenyl)-N',N-dimethy1formamidine hydrochloride crystallized.The mixture was diluted with 400 cc. of acetone and filtered. Theresidue was sucked dry on a funnel and then dried in a desiccator oversulfuric'acid. The product was recrystallized from alcohol, M.P. 261.

Example 5 45 g. of 4-o-tolylazo-o-toluidine and 100 cc. of di-.methylformamide were stirred. 26 g. of thionyl chloride were added at atemperature below 20. The mixture was stirred at room temperature andthen the tempera ture rose to 48. The diazo reaction was negative. Themixture was stirred for an additional 2 hours at room temperature, then300 cc. of acetone were added. The5-o-tolylazo-2-(N,N-dimethylformamidino) toluene hydrochloride wasfiltered ofi, M.P. 198 to 200.

Example 52 15 g. of 4-aminoacetanilide was dissolved in 200 cc. ofboiling acetonitrile and the resulting solution filtered. 15 cc. ofisopropanol-hydrochloric acid 20%) was added to the filtrate whereupon4-aminoacetanilide hydrochloride crystallized. A mixture of 3.8 g. of4-aminoacetanilide hydrochloride, 5 cc. of dimethylfor'mamide and 5 cc.of benzene sulfochloride was heated to tinned heating on a steam bathfor 30 minutes, the reaction mixture was cooled to 30 and diluted with50 cc. of acetone. The resulting crystalline precipitate was filteredoiT yielding 4-(dimethylaminomethyleneamino)acetanilide hydrochloridemelting at 284-285". The free base was obtained by dissolving thehydrochloride salt in water and rendering the resulting solutionalkaline with sodium carbonate. The base crystallizes from water andmelts at 186188. By heating 4 (dimethylaminomethyleneamino)-acetanilidewith hydrochloric acid (1:1) to 95 for a short time, the resultinghydrolyzed compound, 4- (dimethylaminomethyleneamino)aniline wasobtained. It crystallized as the dihydrochloride.

Example 53 Example 54 A mixture of 15 g. of p-thiocyanoaniline, 30 cc.of dimethylformamide and 20 g. of p-toluene sulfochloride was heated ona steam bath to 90 for 30 minutes. The reaction mixture was then dilutedwith 200 cc. of acetone and Following conchilled to 10 whereupon1-(dimethylaminomethyleneamino)-4-thiocyanobenzene hydrochloridecrystallized.

The product was filtered Ofl", washed with acetone and recrystallizedfrom ethanol forming white crystals melting at 215-218.

Reaction of 9 g. of p-thiocyanoaniline hydrochloride, 20 cc. ofdimethylformamide and 10 g. of p-toluene sulfochloride yielded the samecompound, also as white crystals of the hydrochloride melting at 2l5218(recrystallized from ethanol).

Example 55 A mixture of 2.5 g. of -thiocyano-Z-aminobenzophenone, 5 cc.of dimethylforma-mide and 2 g. of p-toluene sulfochloride were heatedtogether at 85 A clear orange colored melt was obtained and was dilutedwith ca. 40 cc. of acetone, whereupon2-(dimethylarninomethyleneamino)-5-thiocyanobenzophenone hydrochloridecrystallized as light yellow crystals melting at 164. The product waswater soluble.

Example 56 34 g. of sulfanilamide, 100 cc. of dimethylformamide and 42g. of benzene sulfochloride were stirred together whereupon the mixtureof the temperature rose to 80. It was then stirred for one hourwhereupon the temperature dropped to 60. Then 300 cc. of ethanol wereadded and the resulting mixture was permitted to stand for 24 hours,after which it was diluted with 400 cc. of water and the resultingprecipitate filtered oil and crystallized from dioxane-water (1: 1)yielding 4-(dirnethylaminomethylenearnino)-benzene sulfonamide as whitecrystals melting at 221-223 Example 58 7.5 g. of1,4,5,8-tetraaminoanthraquinone, 40 cc. of dimethylformamide and 15 cc.of benzene sulfochloride were stirred together whereupon the temperatureof the mixture rose to 55 It was then heated for one hour at 90. Theresulting thick reaction mix was diluted with 100 cc. of acetone at 45and the resulting precipitate filtered oif, yielding1,4,5,8-tetra-(dimethylaminomethyleneamino)-anthraquinone tetra-benzenesulfonate as olive green crystals. By reacting 1.5 g. of1,4,5,8-tetraaminoanthraquinone, 5 cc. of dimethylformamide and 2 cc. ofthionyl chloride,1,4,5,8-tetra-(dimethylaminomethyleneamino)-anthraquinonetetrahydrochloride was obtained as metallic shining crystals. Both thesulfonate and the tetrahydrochloride were soluble in water.

l 4 Example 59 24 g. of 1-amino-4-hydroxy-anthraquinone was stirred with100 cc. of dimethylformamide and with the temperature maintained below20, 15 g. of thionyl chloride was added thereto. The reaction mixturewas then heated at 60 for 2 hours, following which the resultantreaction mix was diluted with 300 cc. of acetone at 40. The resultingprecipitate was filtered off at 20, yielding 1-(dimethylaminomethyleneamino)-4-hydroxy anthraquinone hydrochloride asmetallic shiny crystals melting at 236 (decomp). By using p-toluenesulfochloride, instead of thionyl chloride, the p-toluene sulfonate Wasobtained. It melted at 241 (decomp).

Example 60 25 g. of 2,6-diarnino-3-phenylazopyridine hydrochloride and100 cc. of dimethylformamide were stirred together and 26 g. of thionylchloride was added thereto below 20.

vThe temperature of the mixture then rose to 60 and the mixture wasstirred for two hours at 60, following which it was diluted with 400 cc.of acetone at 40. The resuling solution was chilled to 10 and thenfiltered. The

lter cake so-obtained was dried at 6070 and crystallized fromisopropanol yielding2,6-bis-(N,N-dimethylformamidino)-3-phenylazopyridine dihydrochloride asyellow crystals.

Example 61 A mixture of 20 g. of 4-methylmercaptoaniline hydrochloride,40 cc. of dimethylformamide and 25 g. of ptoluenesulfonyl chloride wereheated on a steam bath to for one hour. The mixture was then cooled to40 and the reaction mass diluted with 350 cc. of acetone, whereuponwhite crystals of N (p methylmercaptophenyl)-N,N-dimethylformamidinep-toluene sulfonate formed and were filtered oil with suction and thenairdried. Upon recrystallization from ethanol, the product melted at211-212".

I claim:

1. A member of the group consisting of a compound of the formula andpharmaceutically acceptable acid addition salts of said compoundswherein R and R -each represents a member of the group consisting ofhydrogen and lower alkyl; R and R each represents a member of the groupconsisting of hydrogen, formamidino, N-lower alkylformamidino,N,N-di-lower alkyl formamidino, and lower alkyl.

2. N,N-di-lower alkyl-N'-(3,4-di-lower alkyl-S-isoxa- 3,073,851 SteigerJan. 15, 1963

1. A MEMBER OF THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA